Project Summary/Abstract: Precise control of synaptic development and connectivity is essential for normal brain functions. Defects in synaptic transmissions lead to the disruption of neuronal circuits, which are the underlying cause of various neuropsychiatric diseases. To understand the in vivo functions of key synaptic regulatory proteins, we have conducted studies on a new mouse model for 14-3-3, which is a family of brain-rich proteins implicated in synaptic functions and genetically linked to schizophrenia. We found that inhibition of 14-3-3 functions in the mouse brain impairs synaptic transmission, and causes a variety of behavioral deficits that correspond to the core endophenotypes of established schizophrenia mouse models. We further identified the NMDA receptor as one of the potential targets of 14-3-3 signaling at excitatory synapses in forebrain neurons. These findings are exciting and suggest that mouse models of 14-3-3 dysfunction may provide unique tools to elucidate synaptic mechanisms underlying the development of schizophrenia-associated behaviors. In this proposal, we will 1) develop more precise animal models to define the brain regional- and developmental- specific contributions of 14-3-3 dysfunctions to behavioral deficits; 2) determine the impact of 14-3-3 dysfunctions on neuronal excitability, synaptic physiology and synchronized network activity in the mouse brain; and 3) delineate the cellular and molecular mechanisms underlying 14-3-3-dependent regulation of synaptic NMDA receptors. This research encompasses expertise, strength and existing resources in our three laboratories. Results from this study will significantly advance our understanding on the synaptic functions of 14-3-3 proteins and their role in mental disorders.